The new insight into the inflammatory response following focused ultrasound-mediated blood-brain barrier disruption.

BACKGROUND: Despite the great potential of FUS-BBB disruption (FUS-BBBD), it is still controversial whether FUS-BBBD acts as an inducing factor of neuro-inflammation or not, and the biological responses after FUS-BBBD triggers the inflammatory process are poorly understood. The aim of this study is to investigate the safety window for FUS levels based on a comprehensive safety assessment. METHODS: The mice were treated with two different ultrasound parameters (0.25 MPa and 0.42 MPa) in the thalamus region of brain. The efficacy of BBB opening was verified by dynamic contrast-enhanced MRI (DCE-MRI) and the cavitation monitoring. The transcriptome analysis was performed to investigate the molecular response for the two BBBD conditions after FUS-mediated BBB opening in time-dependent manners. Histological analysis was used for evaluation of the tissue damage, neuronal degeneration, and activation of glial cells induced by FUS-BBBD. RESULTS: The BBBD, as quantified by the Ktrans, was approximately threefold higher in 0.42 MPa-treated group than 0.25 MPa-treated group. While the minimal tissue/cellular damage was found in 0.25 MPa-treated group, visible damages containing microhemorrhages and degenerating neurons were detected in 0.42 MPa-treated group in accordance with the extent of BBBD. In transcriptome analysis, 0.42 MPa-treated group exhibited highly dynamic changes in the expression levels of an inflammatory response or NF-κB pathway-relative genes in a time-dependent manner whereas, 0.25 MPa was not altered. Interestingly, although it is clear that 0.42 MPa induces neuroinflammation through glial activation, neuroprotective properties were evident by the expression of A2-type astrocytes. CONCLUSIONS: Our findings propose that a well-defined BBBD parameter of 0.25 MPa could ensure the safety without cellular/tissue damage or sterile inflammatory response in the brain. Furthermore, the fact that the excessive sonication parameters at 0.42 MPa could induce a sterile inflammation response via glial activation suggested the possibility that could lead to tissue repair toward the homeostasis of the brain microenvironment through A2-type reactive astrocytes.

Polarization Inverted Ultrasound Transducer Based on Composite Structure for Tissue Harmonic and Frequency Compound Imaging.

Ultrasound transducer with polarization inversion technique (PIT) can provide dual-frequency feature for tissue harmonic imaging (THI) and frequency compound imaging (FCI). However, in the conventional PIT, the ultrasound intensity is reduced due to the multiple resonance characteristics of the combined piezoelectric element, and it is challenging to handle the thin piezoelectric layer required to make a PIT-based acoustic stack. In this study, an improved PIT using a piezo-composite layer was proposed to compensate for those problems simultaneously. The novel PIT-based acoustic stack also consists of two piezoelectric layers with opposite poling directions, in which the piezo-composite layer is located on the front side and the bulk-type piezoelectric layer is located on the back side. The thickness ratio between two piezoelectric layers is 0.5:0.5, but unlike a typical PIT model, it can generate dual-frequency spectrum. A finite element analysis (FEA) simulation was conducted, and subsequently, the prototype transducer was fabricated for performance demonstration. In the simulation and experiment, the intensity was increased by 56.76% and 30.88% compared to the conventional PIT model with the thickness ratio of 0.3:0.7. Thus, the proposed PIT-based transducer is expected to be useful in implementation of THI and FCI.

Verification of Blood-Brain Barrier Disruption Based on the Clinical Validation Platform Using a Rat Model with Human Skull.

Methods to improve drug delivery efficiency through blood-brain barrier disruption (BBBD) based on microbubbles and focused ultrasound (FUS) are continuously being studied. However, most studies are being conducted in preclinical trial environments using small animals. The use of the human skull shows differences between the clinical and preclinical trials. BBBD results from preclinical trials are difficult to represent in clinical trials because various distortions of ultrasound by the human skull are excluded in the former. Therefore, in our study, a clinical validation platform based on a preclinical trial environment, using a human skull fragment and a rat model, was developed to induce BBBD under conditions similar to clinical trials. For this, a human skull fragment was inserted between the rat head and a 250 kHz FUS transducer, and optimal ultrasound parameters for the free field (without human skull fragment) and human skull (with human skull fragment) were derived by 300 mVpp and 700 mVpp, respectively. BBBD was analyzed according to each case using magnetic resonance images, Evans blue dye, cavitation, and histology. Although it was confirmed using magnetic resonance images and Evans blue dye that a BBB opening was induced in each case, multiple BBB openings were observed in the brain tissues. This phenomenon was analyzed by numerical simulation, and it was confirmed to be due to standing waves owing to the small skull size of the rat model. The stable cavitation doses (SCDh and SCDu) in the human skull decreased by 13.6- and 5.3-fold, respectively, compared to those in the free field. Additionally, the inertial cavitation dose in the human skull decreased by 1.05-fold compared to that of the free field. For the histological analysis, although some extravasated red blood cells were observed in each case, it was evaluated as recoverable based on our previous study results. Therefore, our proposed platform can help deduct optimal ultrasound parameters and BBBD results for clinical trials in the preclinical trials with small animals because it considers variables relevant to the human skull.

Interleaved Array Transducer with Polarization Inversion Technique to Implement Ultrasound Tissue Harmonic Imaging.

In ultrasound tissue harmonic imaging (THI), it is preferred that the bandwidth of the array transducer covers at least the fundamental frequency f0 for transmission and the second harmonic frequency 2f0 for reception. However, it is challenging to develop an array transducer with a broad bandwidth due to the single resonance characteristics of piezoelectric materials. In this study, we present an improved interleaved array transducer suitable for THI and a dedicated transducer fabrication scheme. The proposed array transducer has a novel structure in which conventional elements exhibiting f0 resonant frequency and polarization-inverted elements exhibiting 2f0 resonant frequency are alternately located, and the thicknesses of all piezoelectric elements are identical. The performance of the proposed method was demonstrated by finite element analysis (FEA) simulations and experiments using a fabricated prototype array transducer. Using the proposed technique, f0 and 2f0 frequency ultrasounds can be efficiently transmitted and received, respectively, resulting in a 90% broad bandwidth feature of the transducer. Thus, the proposed technique can be one of the potential ways to implement high resolution THI.

A Phase-Canceled Backing Layer for Ultrasound Linear Array Transducer: Modeling and Experimental Verification.

In this study, a phase-canceled backing layer for ultrasound linear array transducer is presented. The proposed backing layer is composed of multiple blocks operated by a phase inversion technique. Inside the proposed backing layer, the phase of the reflected signals can be canceled by adjusting acoustic impedance, piezoelectric layer contact area, and thickness of each block constituting the backing layer. Therefore, the total thickness of the backing layer can be significantly reduced while maintaining the performance. Using finite element analysis (FEA) simulation, its performance was verified based on an 8-MHz linear array transducer. Two types of bulk-type backing layers with different thicknesses were also simulated to compare the performance of the proposed method. In the case of a narrow bandwidth signal without the matching layers, the 10-mm-thick bulk-type backing layer yielded a -6-dB bandwidth of 37.2%. When its thickness was reduced to 2 mm, the -6-dB bandwidth was decreased to 17.3% due to the reflected back-wall signals. However, the -6-dB bandwidth of the proposed backing layer with 2-mm thickness was 39.5%, which is similar to the thick bulk-type backing layer. In the case of broad bandwidth signal with the matching layers, the proposed transducer also exhibits similar performance compared with the thick bulk-type backing layer. The narrow bandwidth signal was experimentally implemented by using a prototype array transducer with the proposed technique, and the performance was similar to the simulation. Thus, the proposed method can reduce the thickness of the backing layer of various array transducers.

Phase-Inverted Multifrequency HIFU Transducer for Lesion Expansion: A Simulation Study.

It has been well known that the treatment time of high-intensity focused ultrasound (HIFU) surgery can be reduced by expanding the focal area per sonication. Previously, a dual-concentric transducer using phase-inverted signals was proposed to axially extend the focal area, but it has suffered from the deep notch point between two focal lobes. In this paper, we propose the improved HIFU transducer with dual-concentric aperture driven by phase-inverted multifrequency signals based on an inversion layer technique. The proposed transducer can generate the expanded focal zone with a significantly reduced level of the notch point between two focal lobes in the axial direction. The performance of the proposed transducer was investigated using finite element analysis simulation. The electrical impedance, one-way impulse response, and acoustic field of the transducer were simulated. Subsequently, the lesion volume was investigated by heat transfer simulation. In the proposed method, the level of the notch point was increased above -6 dB due to various phase interactions between the fundamental and harmonic frequency combinations and the inverted and noninverted frequency combinations. The -6-dB depth of field related to the necrotic lesion size was increased by 141% compared with the conventional single element transducer. Thus, the proposed transducer can be a potential way to enlarge coagulated lesion size resulting in a reduced overall treatment time of HIFU surgery.